The RNA-binding protein musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis

Dat T. Vo, Dharmalingam Subramaniam, Marc Remke, Tarea L. Burton, Philip J. Uren, Jonathan A. Gelfond, Raquel De Sousa Abreu, Suzanne C. Burns, Mei Qiao, Uthra Suresh, Andrey Korshunov, Adrian M. Dubuc, Paul A. Northcott, Andrew D. Smith, Stefan M. Pfister, Michael D. Taylor, Sarath C. Janga, Shrikant Anant, Christine Vogel, Luiz O F Penalva

Research output: Contribution to journalArticle

Abstract

Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.

Original languageEnglish (US)
Pages (from-to)1762-1772
Number of pages11
JournalAmerican Journal of Pathology
Volume181
Issue number5
DOIs
StatePublished - Nov 2012

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Medulloblastoma
RNA-Binding Proteins
Neoplasm Genes
Growth
Carcinogenesis
Ribonucleoproteins
Microarray Analysis
Immunoprecipitation
Heterografts
Cerebellum
Nervous System
Small Interfering RNA
Cluster Analysis
Neoplasms
Stem Cells
Messenger RNA
Genes
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

The RNA-binding protein musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis. / Vo, Dat T.; Subramaniam, Dharmalingam; Remke, Marc; Burton, Tarea L.; Uren, Philip J.; Gelfond, Jonathan A.; De Sousa Abreu, Raquel; Burns, Suzanne C.; Qiao, Mei; Suresh, Uthra; Korshunov, Andrey; Dubuc, Adrian M.; Northcott, Paul A.; Smith, Andrew D.; Pfister, Stefan M.; Taylor, Michael D.; Janga, Sarath C.; Anant, Shrikant; Vogel, Christine; Penalva, Luiz O F.

In: American Journal of Pathology, Vol. 181, No. 5, 11.2012, p. 1762-1772.

Research output: Contribution to journalArticle

Vo, DT, Subramaniam, D, Remke, M, Burton, TL, Uren, PJ, Gelfond, JA, De Sousa Abreu, R, Burns, SC, Qiao, M, Suresh, U, Korshunov, A, Dubuc, AM, Northcott, PA, Smith, AD, Pfister, SM, Taylor, MD, Janga, SC, Anant, S, Vogel, C & Penalva, LOF 2012, 'The RNA-binding protein musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis', American Journal of Pathology, vol. 181, no. 5, pp. 1762-1772. https://doi.org/10.1016/j.ajpath.2012.07.031
Vo, Dat T. ; Subramaniam, Dharmalingam ; Remke, Marc ; Burton, Tarea L. ; Uren, Philip J. ; Gelfond, Jonathan A. ; De Sousa Abreu, Raquel ; Burns, Suzanne C. ; Qiao, Mei ; Suresh, Uthra ; Korshunov, Andrey ; Dubuc, Adrian M. ; Northcott, Paul A. ; Smith, Andrew D. ; Pfister, Stefan M. ; Taylor, Michael D. ; Janga, Sarath C. ; Anant, Shrikant ; Vogel, Christine ; Penalva, Luiz O F. / The RNA-binding protein musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis. In: American Journal of Pathology. 2012 ; Vol. 181, No. 5. pp. 1762-1772.
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abstract = "Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.",
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T1 - The RNA-binding protein musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis

AU - Vo, Dat T.

AU - Subramaniam, Dharmalingam

AU - Remke, Marc

AU - Burton, Tarea L.

AU - Uren, Philip J.

AU - Gelfond, Jonathan A.

AU - De Sousa Abreu, Raquel

AU - Burns, Suzanne C.

AU - Qiao, Mei

AU - Suresh, Uthra

AU - Korshunov, Andrey

AU - Dubuc, Adrian M.

AU - Northcott, Paul A.

AU - Smith, Andrew D.

AU - Pfister, Stefan M.

AU - Taylor, Michael D.

AU - Janga, Sarath C.

AU - Anant, Shrikant

AU - Vogel, Christine

AU - Penalva, Luiz O F

PY - 2012/11

Y1 - 2012/11

N2 - Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.

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